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J. Biol. Chem., Vol. 276, Issue 50, 47650-47657, December 14, 2001
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From the The
cyclin-dependent kinase inhibitor p21Cip1
is up-regulated in response to mitogenic stimulation in various cells.
PPAR
Peroxisome Proliferator-activated Receptor
Ligands Inhibit
Mitogenic Induction of p21Cip1 by Modulating the Protein
Kinase C
Pathway in Vascular Smooth Muscle Cells*
§,¶,,,,
,,, and
Division of Endocrinology, Diabetes, and
Hypertension, School of Medicine, 142-8555 UCLA, Los Angeles,
California 90095, the Institute of Molecular Oncology, Showa
University, Hatanodai, Shinagawa-ku, Tokyo, Japan, and the
** Department of Molecular Microbiology and Immunology,
School of Medicine, University of Southern California,
Los Angeles, California 90033
ligands troglitazone (TRO, 10 µM) and
rosiglitazone (RSG, 10 µM) attenuated the induction of
p21Cip1 protein by platelet-derived growth factor (PDGF)
and insulin without affecting cognate mRNA levels in rat aortic
smooth muscle cells (RASMC). The protein kinase C
(PKC) inhibitor
rottlerin also blocked the induction of p21Cip1 protein,
whereas the conventional PKC isotype inhibitor Gö 6976 had no
effect. Kinetic studies using the protein synthesis inhibitor cycloheximide showed that TRO, RSG, and rottlerin shortened the half-life of p21Cip1 protein. TRO, RSG, and rottlerin
inhibited PDGF-induced expression of p21Cip1, but they did
not affect insulin-induced expression of p21Cip1. Both
ligands inhibited PKC enzymatic activity in PDGF-stimulated RASMC
but not in insulin-stimulated cells. Adenovirus-mediated overexpression
of PKC rescued the down-regulation of p21Cip1 expression
both by TRO and RSG in PDGF-treated RASMC. These data suggested that
the PKC pathway plays a critical role in PDGF-induced expression of
p21Cip1 in RASMC and may be the potential target for
PPAR ligand effects. Src kinase-dependent tyrosine
phosphorylation of PKC was decreased substantially by TRO and RSG.
Tyrosine phosphorylation and activation of c-Src in response to PDGF
were unaffected by either PPAR ligand. Protein-tyrosine-phosphatase inhibitors sodium orthovanadate and dephostatin prevented PPAR ligand effects on PKC tyrosine
phosphorylation and enzymatic activity. Both inhibitors also reversed
PPAR ligand effects on p21Cip1 expression in
PDGF-treated RASMC. PPAR ligands enhanced
protein-tyrosine-phosphatase activity in RASMC, which may be the
mechanism for decreased PKC tyrosine phosphorylation and activity.
PPAR ligands regulate p21Cip1 at a post-translational
level by blocking PKC signaling and accelerating p21Cip1 turnover.
*
This work was supported in part by National Institutes of
Health Grant HL58328-03 (to W. A. H.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Division of
Endocrinology, Diabetes, and Hypertension, UCLA School of Medicine, Warren Hall, Second Floor, Suite 24-130, 900 Veteran Ave., Box 957073, Los Angeles, CA 90095. Tel.: 310-794-7555; Fax: 310-794-7654; E-mail: rlaw@mednet.ucla.edu.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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